UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: April 16, 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Pyraflufen-Ethyl. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 030090 DP Barcode: 0417684 

Decision No.: 487210 Registration No.: NA 

Petition No.: NA Regulatory Action: Registration Review 

Scoping Document 

Risk Assessment Type: NA Case No.: NA 

TXR No.: NA CAS No.: 129630-17-7 

MRID No.: NA 40 CFR: § 180.585 

FROM: Kristin 

Myron Ottley

Rury, 

, 

Biologist 

Senior Toxic \-Q cl~i~ ~(Q~ Nancy Dodd, Chemist ;J~ ,()~ 

Risk Assessment Branch III / 

Health Effects Division (7509P) 

Office of Pesticide Programs ~ 

THROUGH: Christine Olinger, Branch Chief / . 

Risk Assessment Branch III 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Steven Snyderman, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Health Effects Division's (HED) human health Registration Review scoping 

document for the herbicide pyraflufen-ethyl. 

Executive Summary 

HED has evaluated recent human health assessments for pyraflufen-ethyl, ethyl 2-[2-chloro-5-[ 4-

chloro-5-(difluoromethoxy)-1-methyl-lH-pyrazol-3-yl]-4-fluorophenoxy ]acetate, to determine 

whether sufficient data are available and whether any updates are needed to support Registration 

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Review. To determine the scope of work necessary to support Registration Review, HED has 

considered updates to Agency science policy and risk assessment methodologies and to the 

pyraflufen-ethyl toxicity, exposure, and usage databases. 

Pyraflufen-ethyl is a phenyl pyrazole herbicide, registered for agricultural use as a preplant 

burndown application, and as a pre- and post-emergent application. Based on the currently 

registered uses, exposures to pyraflufen-ethyl can be expected to occur via the dietary (food and 

drinking water), occupational (handler and post-application), and residential (handler and postapplication) exposure pathways and via the oral, dermal, and inhalation routes of exposure. 

The registered uses of pyraflufen-ethyl include: pre-plant burndown application to bulb 

vegetables, cereal grains, cole crops, cucurbits, fruiting vegetables, leafy vegetables, legumes, oil 

seeds, root and tuber vegetables, and sugarcane; application to non-bearing dates, feijoa, figs, 

kiwi fruit, mango and persimmon; and in-season application to corn, cotton, grapes, olives, 

peanuts, pistachios, pomegranates, pome fruit (Crop Group 11-1 0), potatoes, small grains, 

soybean, stone fruit (Crop Group 12), tree nuts (Crop Group 14), and wheat. Pyraflufen-ethyl is 

also registered for use in/around non-agricultural areas including: airports; athletic fields; barrier 

strips and fire breaks; Christmas trees; cemeteries; crop stubble; commercial plants; equipment 

areas; fallow beds; fuel tank fanns; golf courses; nurseries; ornamental turf and plantings; rights 

of way; sod farms; storage and lumber yards; pasture and rangeland; and uncultivated 

areas/conservation reserve program areas. 

The pyraflufen-ethyl toxicity database is complete, and no additional toxicity studies are 

required. HED's Hazard and Science Policy Council (HASPOC) determined a subchronic 

inhalation study is not required for pyraflufen-ethyl (D. Smegal, TXR#0054072, 03/02/2012). 

The Food Quality Protection Act (FQPA) safety factor has been reduced to IX because the 

toxicity database is complete, there is no concern for susceptibility in infants and young children, 

there are no neurotoxicity concerns, and there are no residual uncertainties regarding exposure. 

Pyraflufen-ethyl is classified as "Likely to be Carcinogenic to Humans" based on the presence of 

liver tumors (hepatocellular adenomas, carcinomas, and/or hepatoblastomas) in male and female 

mice. There was no evidence of carcinogenicity in male or female rats. There is no 

mutagenicity/genotoxicity concern. A linear low-dose extrapolation approach (Qt* of3.32 x 10-

2 (mg/kg/dayy1

) is used to estimate human cancer risk. The toxicity endpoints and points of 

departure (PODs) and the FQPA Safety Factor will be evaluated during Registration Review. 

A new dietary exposure and risk assessment may be needed during Registration Review to 

incorporate updated estimated drinking water concentrations (EDWCs) into the chronic and 

cancer dietary exposure assessments. At this time, analytical reference standards for the 

pyraflufen-ethyl metabolite E-15 must be submitted to the National Pesticide Standards 

Repository. Additionally, information on sample storage conditions and durations for samples 

analyzed in the orange plant metabolism study was required as a condition of registration. 

Pending resolution of these deficiencies, the residue chemistry and dietary exposure databases 

support the existing uses of pyraflufen-ethyl. 

An updated residential exposure assessment will be needed for pyraflufen-ethyl use on turf and 

ornamentals because there are registered uses of pyraflufen-ethyl in residential areas with higher 

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application rates than those previously assessed. At this time, a turf transferrable residue (TTR) 

study is not required.

An updated aggregate risk assessment will be required to support Registration Review to 

incorporate any new revisions to the drinking water assessment, as well as the findings from the 

updated residential assessment. 

The occupational exposure database is complete. Updated occupational handler exposure 

assessments may be required during Registration Review for all registered crops based upon 

revisions to the Agency’s scenario-specific surrogate handler and post-application exposure data 

and to assess maximum registered single application rates. At this time, a dislodgeable foliar 

residue (DFR) study is not required.

Introduction

Pyraflufen-ethyl is an herbicide belonging to the phenyl pyrazole class of chemicals. Pyraflufenethyl is applied early in the crop growth cycle to control weeds around agricultural crops and

non-residential areas. Pyraflufen-ethyl is sold in the United States as liquid (including ready-touse) and dry flowable (DF)/water-dispersible granule (WDG) formulations. For information on 

the chemical identity of pyraflufen-ethyl, see Attachment 1. 

The most recent risk assessment for pyraflufen-ethyl was conducted to evaluate the proposed use 

on hops and peanuts in 2012 (K. Rury, D396779, 10/01/2012). 

Hazard Identification/Toxicology

The pyraflufen-ethyl hazard database was reviewed in the previous risk assessment and 

considered complete (K. Rury, D396779, 10/01/2012). Toxicity endpoint and profile tables are 

included in Attachments 3 and 4. 

Pyraflufen-ethyl exhibits low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity 

Category III), and inhalation (Toxicity Category IV) routes of exposure. It produces moderate 

eye irritation (Toxicity Category III), and is not a dermal irritant or a dermal sensitizer. 

Following repeated short-term and chronic oral doses, the liver, kidney, and hematopoietic 

system are the target organs for pyraflufen-ethyl in the rat and/or mouse. Adverse effects were 

not noted in the dog following oral exposure or in the rat following dermal exposure. There was 

no evidence of increased susceptibility following pre-natal exposure to rats and rabbits in the 

developmental toxicity studies, or following pre- and post-natal exposure to rats in the multigeneration reproduction study. There was no concern for neurotoxicity or immunotoxicity in the 

pyraflufen-ethyl database. Effects seen in the acute neurotoxicity study (transient decrease in 

body weight gain) and the immunotoxicity study (decreases of anti-SRBC AFC response in male 

rats) occurred only at the limit dose. Pyraflufen-ethyl is classified as “Likely to be Carcinogenic 

to Humans” based on the presence of liver tumors (hepatocellular adenomas, carcinomas, and/or 

hepatoblastomas) in male and female mice. There was no evidence of carcinogenicity in male or 

female rats. There is no mutagenicity/genotoxicity concern. A linear low-dose extrapolation 

approach (Q1* of 3.32 x 10-2(mg/kg/day)-1) is used to estimate human cancer risk (J. Kidwell, 
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TXR#0050930, 10/08/2002). Based on the available data, toxicity endpoints and PODs have 

been selected for chronic dietary, incidental oral (short- and intermediate term), and inhalation 

(all time periods) exposure scenarios.

The FQPA safety factor (infants and children) has been reduced to 1X for acute, short-term, 

intermediate-term, and chronic risk assessments, based on the following considerations: 1) the 

toxicity database for pyraflufen-ethyl is complete and considered adequate for risk assessment; 

2) there are no concerns for neurotoxicity and no need for a developmental neurotoxicity study; 

3) there are no residual uncertainties for pre- and/or postnatal exposure since there is no evidence 

of increased susceptibility following in utero exposure in the developmental studies in the rat and 

rabbit, or increased susceptibility following pre- and post-natal exposure in the reproduction 

study in the rat; and 4) there are no residual uncertainties identified in the exposure databases. 

Conclusion: The toxicity database is adequate to support existing registrations. No 

modifications to the endpoint selections and safety factors are required during Registration 

Review.

Dietary Exposure

At this time, analytical reference standards for the pyraflufen-ethyl metabolite E-15 must be 

submitted to the National Pesticide Standards Repository. Additionally, information on sample 

storage conditions and durations for samples analyzed in the orange plant metabolism study was 

required as a condition of registration. Pending resolution of these deficiencies, the residue 

chemistry and dietary exposure databases will be complete. 

Tolerance enforcement methods are available for determining residues of pyraflufen-ethyl and 

metabolite E-1 in/on plant commodities. Field trial data generated using acceptable data 

collection methods and supported by adequate storage stability data are available for all 

registered crops. Adequate processing studies are available. Adequate livestock feeding studies 

have been submitted for pyraflufen-ethyl.

HED has concluded that the residues of concern in plants include the parent and pyraflufen 

(metabolite E-1) for purposes of tolerance enforcement and risk assessment. HED previously 

concluded that the residues of concern in livestock commodities are parent and metabolites E-1 

and E-9 (refer to names and structures in Appendix 1), and that all three compounds should be 

measured in livestock feeding studies. Based on the metabolite E-9 results of the livestock 

feeding study, HED concludes that the tolerance expression for livestock commodities includes

parent and metabolites E-1 and E-9. 

Environmental fate data indicate that metabolites E-1 and E-2 (refer to Appendix 1) are the 

major metabolites (>10% total radioactive residues [TRR]) in photolysis, aerobic soil 

metabolism, anaerobic aquatic metabolism and aerobic aquatic metabolism studies for parent. 

Metabolite E-3 is the major metabolite (>10% TRR) in aerobic soil metabolism resulting from 

metabolite E-2. 
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There were no adverse effects attributable to a single dose; therefore, an acute dietary exposure 

assessment was not performed. Pyraflufen-ethyl is classified as “Likely to be Carcinogenic to 

Humans” by the oral route; therefore, a cancer dietary risk assessment is required in addition to a 

chronic dietary assessment. 

Partially refined chronic and cancer dietary assessments were conducted using 100% crop treated 

and using 1⁄2 the limit of quantification (LOQ) for the residue values because all available 

pyraflufen-ethyl field trials showed residues less than the LOQ including the metabolites for the 

following commodities: corn, cottonseed, potato, soybean, wheat, pome fruit, stone fruit, 

pomegranate, olive, grape, tree nuts, and pistachio. All other established and proposed 

commodities were analyzed using tolerance-level residues. Anticipated residues were used for 

livestock commodities. Because the commodity-specific processing studies did not show 

pyraflufen-ethyl concentration after processing, only default processing factors were used for dry 

potatoes (6.5X), peanut butter (1.89X), dried beef (1.92X), and corn syrup (1.5X). An empirical 

processing factor of 0.6X was used for cotton seed oil. All exposure inputs for the cancer 

assessment were the same as for the chronic dietary exposure assessment, except the EDWC. 

The dietary assessments were conducted using the Dietary Exposure Evaluation Model (DEEMFCID) using food consumption data from the U.S. Department of Agriculture’s (USDA) 

National Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA). 

The chronic dietary (food and drinking water) exposure to pyraflufen-ethyl is below HED’s level 

of concern (LOC) [i.e., <100% of the chronic population adjusted dose (cPAD)] for the general 

U.S. population and all population subgroups. The chronic dietary exposure estimates utilize 

<1% of the cPAD for the general U.S. population and all population subgroups, including 

children 1-2 years old, the most highly exposed population subgroup. 

Cancer dietary exposure from drinking water was determined based on a Tier 2 drinking water 

(surface water) estimate provided by EFED. The EDWC estimate (30-year average) value of 

0.268 ppb for the combined residues of pyraflufen-ethyl and its metabolic products, E-1, E-2, 

and E-3 were incorporated directly into the dietary assessment to estimate carcinogenic risk from 

drinking water containing pyraflufen-ethyl. The cancer dietary (food and drinking water) risk 

estimate for pyraflufen-ethyl is 2x10-6. Pyraflufen-ethyl residue estimates on cereal grains, root 

and tuber vegetables, and tuberous and corm vegetables were the highest contributors to the 

cancer dietary exposure estimate. 

Conclusion: A new dietary exposure assessment may be needed during Registration Review to 

incorporate any changes to the drinking water exposure estimates. If the EDWCs increase, the 

cancer dietary exposure estimates are likely to be greater than 2x10-6. 

Residential Exposure

Pyraflufen-ethyl is currently registered for use by residential and commercial applicators on 

several residential/non-agricultural use sites; i.e., established ornamental turf lawns, parks, 

cemeteries, athletic fields, golf courses, sod farms, nurseries and ornamental plantings, and 

christmas trees. It is assumed that most residential uses will result in short-term (1-30 day) 
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exposures. Residential handlers are assumed to be wearing short-sleeved shirts, short pants, 

shoes, and socks during pyraflufen-ethyl application. Because there was no dermal endpoint 

chosen for pyraflufen-ethyl, non-cancer handler risk from exposure to pyraflufen-ethyl was 

assessed for the inhalation route only. All residential handler margins of exposure (MOEs) were 

not of concern to HED, and greater than 35,000,000. Post-Application incidental oral margins of 

exposure were not of concern to HED and were greater than 270,000. Cancer risk estimates 

(dermal + inhalation) were assessed for residential handlers only. It was assumed for cancer risk 

assessment that a handler could treat turf only twice per year based on the maximum number of 

applications recommended on the registered labels. Residential handler cancer (dermal + 

inhalation) risk estimates ranged from 2.0x10-8 to 2.1x10-7. Adult post-application cancer risk 

estimates from contact with treated turf and ornamentals ranged from 1.5x10-8to 7.6x10-7. 

An updated residential exposure assessment will be needed for pyraflufen-ethyl use on turf and 

ornamentals because there are registered uses of pyraflufen-ethyl in residential areas with higher 

application rates than those previously assessed; therefore, all existing uses will be reevaluated 

with the updated Residential SOPs during Registration Review.

Residential exposures resulting from off-site transport (e.g., spray drift or volatilization) may 

occur as a result of applications of pyraflufen-ethyl. The Agency is in the process of evaluating 

these types of exposures and may, as appropriate, develop policies and procedures to identify the 

need for and, subsequently, the way to incorporate these post-application exposures into the 

Agency's risk assessments. The need for spray drift and volatilization risk assessments for 

pyraflufen-ethyl will be examined during Registration Review.

Conclusions: An updated residential handler and post-application assessment will be needed for 

pyraflufen-ethyl during Registration Review. HED will also consider volatilization exposure, as 

well as the potential for exposure from spray drift, during Registration Review.

In accordance with 40CFR158, TTR data are required for all occupational (e.g., sod farms, golf 

courses, parks, and recreational areas) or residential turf uses that could result in post-application 

exposure to turf. In the absence of chemical-specific TTR data, EPA uses default values. The 

2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an 

analysis of all TTR data, available at the time, which resulted in the selection of revised liquid 

and granular default values for the fraction of the application rate available for transfer after a 

turf application (FAR). These values are based on an analysis of 59 TTR studies performed with 

the Modified California Roller Method (36 studies using liquids, 11 studies using wettable 

powders/water dispersible granules, and 12 studies using granules). The liquid results (N=131) 

indicate a range of FAR values from 0.0005% to 6.1% and the granular results (N=37) indicate a 

range of 0.00064% to 0.69%. In both the liquid and granular data, a large range of transferability 

is observed and this variability can potentially be attributable to many factors such as active 

ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or 

many other difficult to quantify factors. Although witnessed across multiple chemicals, this 

range in FAR values is not expected when considering TTR data for a single chemical. EPA 

selected 1% and 0.2% as the reasonable, high-end default values for liquid and granular 

products, respectively. Because TTR data are not available for pyraflufen-ethyl, EPA has used 

the default value of 1%. Although there may be a small degree of uncertainty in the use of the 
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default TTR value for pyraflufen-ethyl (i.e., there is a small chance that the FAR value may 

exceed the applicable default value), it is likely that the health-protective aspects of EPA’s 

residential post-application turf assessment methodology will more than compensate for this 

potential uncertainty. For example, when assessing residential post-application turf exposure, 

EPA assumes the following: exposures occur to zero-day (i.e., day of application) residues every 

day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation 

occurs, it doesn’t rain, the grass is not mowed, etc); individuals perform the same postapplication activities performed in the turf transfer coefficient study day after day (e.g., 

tumbling, playing on turf with toys, etc.); and individuals engage in these post-application 

activities for a high-end amount of time every day (represented by data reflecting time children 

spend outdoors and not specifically engaged in activities on turf). In actuality, residues will 

dissipate to some degree depending on the chemical; children do not play on turf every day; 

children do not spend all of their outdoor time on turf; and high-end levels of activity will not 

occur every day even if children are playing on treated turf. 

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. Since the estimated residential turf post-application 

exposure using default TTR values for pyraflufen-ethyl is minimal in comparison to the level of 

concern (i.e., the calculated MOE is greater than 10 times higher than the level of concern, MOE 

= 270,000 compared to the LOC of 100); EPA is waiving the 40CFR TTR data requirement. In 

this instance, it is unlikely that chemical-specific TTR data would be needed to further refine 

exposure assessments or would add appreciably to our overall understanding of the availability 

of turf transferable pesticide residues for pyraflufen-ethyl. 

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are 

required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 

Standard Operating Procedures for Residential Pesticide Exposure Assessment, HED analyzed a 

number of DFR studies and selected a new default value for the fraction of the application rate 

available to be dislodged after a foliar application (FAR). This default value is 25% and is based 

on an analysis of 19 DFR studies where the FAR value ranged from 2% to 89%. This value is 

recommended for use in both residential and occupational postapplication assessments. Of the 

analyzed DFR studies, the maximum FAR value seen was 89% or 3.6 times higher than the 

default residue transfer value. Therefore, the HED has decided that a calculated MOE of 

approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) 

using the default dislodged residue values would provide an adequate margin of safety for any 

potentially higher residues seen in a chemical-specific DFR study (Guidance for 

Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) 

Studies. 12/12/2012, Exposure Science Advisory Council). A DFR study is not required for 

pyraflufen-ethyl at this time since the there is no hazard via the dermal route of exposure and a 

non-cancer dermal post-application risk assessment was not performed. Therefore, DFR studies 

are not needed for pyraflufen-ethyl at this time. If the PODs change, the need for DFR studies 

may be reevaluated in the future to refine the post-application assessment. 
Page 8 of 25

Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are residential uses of pyraflufen-ethyl, aggregate risk for all exposure durations 

consists of residential handler and post-application exposures, food, and drinking water. For 

pyraflufen-ethyl, no adverse effects attributable to a single dose were observed in oral toxicity 

studies, including developmental toxicity studies in rats and rabbits. Therefore, an acute 

reference dose has not been established and an acute aggregate risk assessment is not required. 

In the most recent human health risk assessment (K. Rury, D396779, 10/01/2012), short-term 

aggregate risk estimates resulting from residential, food, and drinking water exposure were not 

of concern. In addition, the aggregate cancer risk assessment considers exposure estimates from 

dietary consumption of pyraflufen-ethyl in food and drinking water, and exposure through 

residential uses. The aggregate cancer risk estimate for pyraflufen-ethyl was 2.6x10-6in the 

previous risk assessment (K. Rury, D396779, 10/01/2012). 

Conclusions: Because a new dietary exposure assessment will be needed during Registration 

Review to incorporate changes to the drinking water exposure estimates, and because the 

residential exposure estimates will be reevaluated, an updated aggregate risk assessment will be 

conducted during Registration Review. If the EDWCs increase, the cancer aggregate exposure 

estimates are likely to be greater than 2.6x10-6. 

Occupational Exposure and Risk

Pyraflufen-ethyl is a phenyl pyrazole herbicide, registered for agricultural use as preplant 

burndown applications, applications after planting but before crop emergence, and post-emergent 

applications. Registered agricultural use sites include: bulb vegetables, cole crops, corn, cotton, 

cucurbits, fallow beds and crop stubble, dates, feijoa, figs, fruiting vegetables, grapes, grasses, 

kiwi, leafy vegetables, legumes, mango, non-crop areas, olives, oil seeds, pasture and rangeland, 

peanuts, persimmons, pistachios, pomegranates, pome fruit (Crop Group 11-10), potatoes, root 

and tuber vegetables, small grains, soybean, stone fruit (Crop Group 12), sugarcane, tree nuts 

(Crop Group 14), uncultivated areas/conservation reserve program areas, and wheat. 

Pyraflufen-ethyl is also registered for occupational use on the following non-agricultural use 

sites: airports, barrier strips and fire breaks, Christmas trees, commercial plants, equipment areas, 

fuel tank farms, golf courses, nurseries, ornamental turf, rights of way, sod farms, and storage 

and lumber yards. 

Pyraflufen-ethyl is formulated as liquids, dry flowable, and as a ready-to-use solution. 

Pyraflufen-ethyl may be applied using aerial, ground, and hand-held spray equipment. The 

personal protective equipment (PPE) required for handlers consists of a single layer of clothing 

(long sleeve shirt, long pants, and socks plus shoes), chemical resistant gloves, and in some 

cases, protective eyewear. The restricted entry interval (REI) for pyraflufen-ethyl is 12 hours.

The occupational uses of pyraflufen-ethyl are expected to result in both short- and intermediateterm exposures. Occupational exposure assessments have been conducted for pyraflufen-ethyl 

liquid and dry flowable formulations.
Page 9 of 25

Previous occupational handler exposure and risk assessments were conducted for pyraflufenethyl use on corn, cotton, grapes, grasses, non-crop areas, olives, pasture and rangeland, pome 

fruit, pomegranates, potatoes, soybeans, stone fruit, tree nuts, turf and wheat. All current 

exposure estimates at baseline PPE (single layer clothing, no gloves, and no respirator) result in 

both non-cancer and cancer risk estimates which are not of concern. The occupational handler 

inhalation MOEs for the uses evaluated were not of concern to HED and were greater than 

190,000. To assess cancer risk, it is assumed that private growers would be exposed 10 days per 

year and commercial applicators would be exposed 30 days per year. The term “private grower” 

means that the grower or one of the workers would apply the pesticides to land owned or 

operated by the grower. Commercial applicators means the applicators are completing multiple 

applications for multiple clients. Occupational handler cancer (dermal + inhalation) risk 

estimates at baseline PPE (no gloves) ranged from 3.5x10-8to 6.1x10-5. When evaluated, 

occupational handler cancer (dermal + inhalation) risk estimates with gloves ranged from 2.2x10-

8

to 3.3x10-6.

However, these assessments were not conducted at the maximum registered application rates and 

using the current occupational exposure inputs; therefore, a new occupational exposure 

assessment may be conducted for these uses and all the registered occupational uses of 

pyraflufen-ethyl during Registration Review. 

Occupational post-application exposure can occur via the dermal and/or inhalation route. Postapplication non-cancer dermal exposures to pyraflufen-ethyl were not evaluated because adverse 

effects were not seen in the subchronic 28-day dermal toxicity study up to the Limit Dose (1,000 

mg/kg/day). Post-application cancer (dermal + inhalation) risk was estimated for use on peanuts

(scouting only) and treated lawns. HED assumes that post-application workers would be 

exposed 30 days per year. These risk estimates ranged from 5.0x10-8to 2.2x10-6on the day of 

application. However, occupational post-application exposure inputs and policies have changed

since the previous risk assessments and post-application exposure from registered uses of 

pyraflufen-ethyl may be re-evaluated during Registration Review. 

Based on the Agency's current practices, a quantitative non-cancer post-application inhalation 

exposure assessment was not performed for pyraflufen-ethyl at this time primarily because of the 

low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (1.2x10-10 mm Hg), and 

the low registered use rates. However, there are multiple potential sources of post-application 

inhalation exposure to individuals performing post-application activities in previously treated 

fields. These potential sources include volatilization of pesticides and resuspension of dusts 

and/or particulates that contain pesticides. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Re-Entry Task Force (ARTF) and may, as appropriate, 

develop policies and procedures, to identify the need for and, subsequently, the way to 

incorporate occupational post-application inhalation exposure into the Agency's risk 

assessments. If new policies or procedures are put into place, the Agency may revisit the need 
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for a quantitative occupational post-application inhalation exposure assessment for pyraflufenethyl.

The pyraflufen-ethyl database lacks DFR studies. In accordance with the updated Part 158 data 

requirements (2007), one or more DFR studies are required when a pesticide has residential or 

occupational uses that could result in post-application dermal exposure. Because there is no 

hazard via the dermal route of exposure, a non-cancer dermal post-application risk assessment 

was not performed for pyraflufen-ethyl. Therefore, DFR studies are not needed for pyraflufenethyl at this time. If the PODs change, the need for DFR studies may be reevaluated in the future 

to refine the post-application assessment. 

Conclusions: There is sufficient information available to assess occupational exposure. An upto-date occupational assessment may be needed for all existing uses of pyraflufen-ethyl to 

account for changes in occupational assessment policies (unit exposures and transfer 

coefficients) and to evaluate the maximum registered single application rate for each use site. 

Public Health and Pesticide Epidemiology Data

Based on the low frequency and severity of incident cases reported for pyraflufen-ethyl in both 

the OPP Incident Data System (IDS) and Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR)-Pesticides, there does not appear to be a concern at 

this time that would warrant further investigation. There were only eight aggregate incidents 

(minor, unknown, or no effect outcomes) involving pyraflufen-ethyl reported in the Aggregate 

IDS, from January 1, 2009 to January 15, 2014. A query of SENSOR-Pesticides 1998-2010 

identifies one case involving pyraflufen-ethyl which occurred in Washington State in 2005. This 

case involved multiple active ingredients (the two products implicated are Vanquish Herbicide 

and ET Herbicide/Defoliant). 

The Agency will continue to monitor the incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

The current tolerance expression for pyraflufen-ethyl is appropriate. Tolerances are established 

for plant and livestock commodities under 40 CFR §180.585(a) for residues of the herbicide 

pyraflufen-ethyl, including its metabolites and degradates. Compliance with the plant 

commodity tolerance levels specified is to be determined by measuring only the sum of the 

parent pyraflufen-ethyl, ethyl 2-[2-chloro-5-(4-chloro-5-difluoromethoxy)-1-methyl-1H-pyrazol3-yl]-4-fluorophenoxy] acetate, and its acid metabolite, E-1, 2-chloro-5-(4-chloro-5-

difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, calculated as the 

stoichiometric equivalent of pyraflufen-ethyl in or on the commodity. Compliance with the 

livestock commodity tolerance levels is to be determined by measuring only the sum of the 

parent pyraflufen-ethyl and its acid metabolites: E-1 and E-9, 2-chloro-5-(4-chloro-5-

difluoromethoxy-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, both calculated as the 

stoichiometric equivalent of pyraflufen-ethyl in or on the commodity.
Page 11 of 25

The stone fruit and tree nut crop group commodity definitions should be updated from Fruit, 

stone, group 12 to Fruit, stone, group 12-12, and from Nut, tree, group 14 to Nut, tree, group 14-

12. Since the representative crops for these crop groups have not changed, no additional residue 

data are needed to update these crop group names. 

There are no Codex or Canadian maximum residue limits (MRLs) established for pyraflufenethyl; therefore, there is no harmonization issue at this time. 

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf). As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the United States Department of 

Agriculture’s (USDA’s) National Health and Nutrition Examination Survey (NHANES), What 

We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, 

specialized subgroups and exposure assessments are performed when conditions or 

circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of 

pesticide products and associated risks for adult applicators and for toddlers, youths, and adults 

entering or playing on treated areas following application are evaluated. Further considerations 

are currently in development as OPP has committed resources and expertise to the development 

of specialized software and models that consider exposure to bystanders and farm workers as 

well as lifestyle and traditional dietary patterns among specific subgroups.

Cumulative Risk Assessments 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to pyraflufen-ethyl and any other substances, and pyraflufen-ethyl does not appear to produce a 

toxic metabolite produced by other substances. For the purposes of this tolerance action, 

therefore, EPA has not assumed that pyraflufen-ethyl has a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s OPP concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

Human Studies
Page 12 of 25

Past pyraflufen-ethyl risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal and inhalation 

exposure. These data, which include studies from the Pesticide Handlers Exposure Database 

Version 1.1 (PHED 1.1); the ARTF database; the Outdoor Residential Exposure Task Force 

(ORETF); and other registrant-submitted exposure monitoring studies, are subject to ethics 

review pursuant to 40 CFR 26, have received that review, and are compliant with applicable 

ethics requirements. For certain studies that review may have included review by the Human 

Studies Review Board. Descriptions of data sources as well as guidance on their use can be 

found at http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html.

Data Requirements

Residue Chemistry

860.1650 Submittal of Analytical Reference Standards 

Analytical reference standards for pyraflufen-ethyl and metabolite E-15 must be submitted to the 

National Pesticide Standards Repository. (E-mail from Theresa Cole, 1/9/14: Pyraflufen-ethyl is 

out of stock. Metabolite E-15 expired on 10/18/13. Metabolites E-1 and E9 are available, with 

expiration dates of 7/2/16 and 4/3/15, respectively.) 

860.1300 Nature of the Residue – Plants

The petitioner should submit information on sample storage conditions and durations for samples 

analyzed in the orange plant metabolism study (MRID 47872706, discussed in D377359).

References

Memoranda Relevant to Registration Review of Pyraflufen-ethyl

Author DP/TXR# Date Title

Risk Assessment

K. Rury D396779 10/01/2012 Pyraflufen-ethyl – Human Health Risk Assessment for a Section 3 

Registration of New Food Uses on Hops and Peanuts.

K. Rury D388220 03/31/2011 Pyraflufen-Ethyl: Addendum to Human Health Risk Assessment

for a Section 3 Registration of New Food Uses on Tree Nuts (Crop

Group 14), Pistachios, Pome Fruit (Crop Group 11-10), and Stone

Fruits (Crop Group 12), Hops, Grapes, Olives and Pomegranates. 

K. Rury D377359 03/01/2011 Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3

Registration of New Food Uses on Tree Nuts (Crop Group 14),

Pistachios, Pome Fruit (Crop Group 11-10), and Stone Fruits (Crop

Group 12), Hops, Grapes, Olives and Pomegranates. 

K. Rury D361213 02/24/2010 Pyraflufen-ethyl: Human Health Risk Assessment for a Section 3 

Registration of New Non-Food Uses on Established Ornamental 

Turf Lawns (Residential, Industrial, and Institutional), Parks, 

Cemeteries, Athletic Fields, Golf Courses (Fairways, Aprons, Tees 

and Roughs), Sod farms, and Similar Turf Areas.

M. Ottley D337842 04/17/2008 Pyraflufen-ethyl: Human Health Risk Assessment for Pyraflufen-
Page 13 of 25

Memoranda Relevant to Registration Review of Pyraflufen-ethyl

Author DP/TXR# Date Title

ethyl: Proposed New Use on Pasture and Rangeland Grasses

(PP#7F7190) and Amendment to Allow Early Season

Postemergence Broadcast Uses to Corn (excluding sweet corn),

Soybeans, and Wheat and Proposed Increased Tolerances on

Soybean Forage and Hay (PP#1F6248).

H. Johnson D299196 04/07/2004 PP#1F06248 Human Health Risk Assessment for Pyraflufen-ethyl

on Wheat.

M. Rust D283496 01/24/2003 Pyraflufen-ethyl. Amendment to PP#1F06248. Human Health Risk

Assessment for Uses on Field Corn and Soybeans.

M. Rust D286618 11/06/2002 PP#1F06248 Human Health Risk Assessment for Pyraflufen-ethyl

on Cotton and Potatoes.

Residue Chemistry

A. Acierto D396779 09/12/2012 (Amended) Pyraflufen-ethyl. PP#1F7944. Petition for

Establishment of Tolerances on Hops and Peanuts; Multi-Residue

Method (MRM) and Independent Laboratory Validation (ILV);

Unconditional Registrations for Use on Pastures, Rangeland and

Post Emergence Application to Corn, Soybean and Wheat; and

Amended Report for Residues in Bovine Tissues and Milk from a

28-day Feeding Study Data, Radiovalidation in Goat Liver and Milk

and Storage Stability. Summary of Analytical Chemistry and

Residue Data.

L. Cheng D377361 02/07/2011 Pyraflufen-ethyl: Proposed New Use on Pome Fruit (crop group

11), Stone Fruit (crop group 12), Pomegranates, Olives, Hops,

Grapes, Tree Nuts (crop group 14), and Pistachios. Summary of

Analytical Chemistry and Residue Data.

A. Acierto D364053 06/26/2009 Pyraflufen-ethyl: Petition for Label Amendments to Add Aerial

Application to Pre-plant Burndown Uses of Pyraflufen-ethyl on

Bulb Vegetables, Leafy Vegetables, Brassica Leafy vegetables,

Cole Crops, Cucurbit Vegetables, Fruiting Vegetables, Legume

Vegetables, Root and Tuber Vegetables, Cereal Grains, Oil Seed

Crops, and Sugarcane.

M. Negussie D356829 01/26/2009 Pyraflufen-ethyl: Petition for a Label amendment for new Non-Food

Uses on Bulb Vegetables, Oil Seed Crops, Cereal Grain Crops, and

Sugarcane.

B. CroppKohligianD339032 01/30/2008 Pyraflufen-ethyl. PP#7F7190: Proposed New Use on Pasture and

Rangeland Grasses. PP#1F6248: Amendment to Allow Early

Season Postemergence Broadcast Uses to Corn (excluding sweet

corn), Soybeans, and Wheat and Proposed Increased Tolerances on

Soybean Forage and Hay. Summary of Analytical Chemistry and

Residue Data.

L. Cheng D320103 10/31/2006 Pyraflufen-ethyl. Supplemental Data to Support Amended Use on

Cotton and Established Use on Wheat (PRIA R35). Summary of

Analytical Chemistry and Residue Data.

Dietary Exposure

K. Rury D397422 09/09/2012 Pyraflufen-ethyl: Chronic and Cancer Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the Section 3 

Registration Action on Hops and Peanuts.

A. Acierto D347500 03/25/2008 Pyraflufen-ethyl. Chronic Aggregate (Food and Drinking Water) 

Dietary Exposure and Risk Assessments for a Section 3 Registration 

Action to Allow Early Season Postemergence Uses on Corn 

(Excluding Sweet Corn), Soybeans, and Wheat. 
Page 14 of 25

Memoranda Relevant to Registration Review of Pyraflufen-ethyl

Author DP/TXR# Date Title

H. Johnson D299196 03/01/2004 Pyraflufen-ethyl Chronic Dietary Exposure Assessment for the 

Section 3 Registration Action.

L. Cheng D285317 10/17/2002 Pyraflufen-Ethyl Chronic and Cancer Dietary Exposure 

Assessments for the Section 3 Registration Action.

Occupational Residential Exposure

M. Rust D278144 09/12/2002 Nonfood Use Risk Assessment to Support Request for a Section 3 

Registration for the Use of Pyraflufen Ethyl on Non-crop Areas. 

M. Rust D286617 10/23/2002 PYRAFLUFEN-ETHYL: Occupational and Residential Exposure 

Assessment to Support Request for Use on Potatoes and Cotton.

M. Rust D287401 12/20/2002 PYRAFLUFEN-ETHYL: Occupational Exposure Assessment to 

Support Request for New Uses on Soybeans, Wheat and Corn.

M. Dow D299666 03/25/2004 PYRAFLUFEN ETHYL - Exposure/Risk Assessment for the 

Proposed Use of Pyraflufen Ethyl on Wheat.

M. Dow D339033 08/09/2007 PYRAFLUFEN-ETHYL - Occupational Exposure/Risk Assessment 

for the Proposed Use of Pyraflufen-ethyl on Pasture and Range 

Grass and Post-Emergence Use on Corn, Soybean and Wheat.

K. Rury D361213 01/14/2010 Pyraflufen-ethyl: Occupational and Residential Exposure 

Assessment for proposed non food uses of pyraflufen-ethyl on cool 

season grasses (bluegrass, fescue, and ryegrass) and warm season 

grasses (bahiagrass, common bermudagrass, centipedegrass, St. 

Augustinegrass, and zoysiagrass).

K. Rury D378642 12/14/2010 Pyraflufen-Ethyl: Occupational and Residential Exposure 

Assessment for proposed uses of pyraflufen-ethyl on the tree nut, 

pome fruit, and stone fruit crop groups, hops, grapes, olives and 

pomegranates. 

K. Rury D397423 10/01/2012 Pyraflufen-ethyl. Occupational and Residential Exposure 

Assessment for a Proposed Use on Hops and Peanuts and a 

Reevaluation of Existing Residential Uses with the Updated 

Residential SOPs.

Toxicology

D. Smegal TXR 

0054072

03/02/2012 Pyraflufen-ethyl: Summary of Hazard and Science Policy Council 

(HASPOC) Meeting of February 16, 2012: Recommendations on a 

waiver request for a 28-day inhalation study.

Incident Report

S. Recore D418062 02/12/2014 Revised: Pyraflufen-Ethyl: Tier 1 Review of Human Incidents.

Attachments

Attachment 1. Chemical Identity Table

Attachment 2. International Residue Limit Status

Attachment 3. Pyraflufen-Ethyl Endpoint Selection Tables

Attachment 4. Pyraflufen-Ethyl Toxicity Profiles
Page 15 of 25

Attachment 1

Chemical Identity Table

Table 1. Pyraflufen-Ethyl and Its Metabolites Nomenclature.

Chemical structure

Common name pyraflufen-ethyl

PC Code 030090

Company experimental name ET-751

IUPAC name ethyl [2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-

fluorophenoxy]acetate

CAS name ethyl 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetate

CAS registry number 129630-19-9

End-use product (EP) 0.208 lb/gal EC (2.5% EC; ET® Herbicide/Defoliant; EPA Reg. No. 71711-7;

Label Date 02/20/2007)

0.17 lb/gal FlC (2.0% FlC; ET® 2%SC Herbicide/Defoliant; EPA Reg. No. 71711-25;

Label Date 09/06/2007)

Chemical structure 

Common name pyraflufen

PC Code 030091

Company experimental name Metabolite E-1; Pyraflufen-ethyl plant and livestock metabolite of concern

IUPAC name [2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-fluorophenoxy]acetic acid

CAS name 2-[2-chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-

fluorophenoxy]acetic acid

CAS registry number 129630-17-7

N N

Cl

F

Cl

CH

3

OCHF

2

OCH

2

COOH

N N

Cl

F

Cl

CH

3

OCH

2

COOC

2

H

5

OCHF

2
Page 16 of 25

Table 1. Pyraflufen-Ethyl and Its Metabolites Nomenclature.

Chemical structure

Company experimental name Metabolite E-2; 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)-4-

fluorophenol

Chemical structure 

Company experimental name Metabolite E-9; Pyraflufen-ethyl livestock metabolite of concern; 2-[2-chloro-5-[4-chloro-5-

(difluoromethoxy)-1H-pyrazol-3-yl]-4-fluorophenoxy]acetic acid

Chemical structure 

Company experimental name GC/MSD Residue Method Analyte E-15; methyl ester of Metabolite E-1; methyl 2-[2-

chloro-5-[4-chloro-5-(difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy]acetate

N N

Cl

F

Cl

CH

3

OCHF

2

OCH

2

COOCH3

N N

Cl

F

Cl

H

OCHF

2

OCH

2

COOH
Page 17 of 25

Attachment 2

Tolerance/MRL Table

Pyraflufen-ethyl (030090)

Table 2. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: (a) General. Plants: the sum of the parent pyraflufen-ethyl, ethyl 2-[2-chloro-5-(4-chloro-5-

difluoromethoxy)-1-methyl-1H-pyrazol-3-yl]-4-fluorophenoxy] acetate, and its acid metabolite, E-1, 2-chloro-5-(4-

chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, calculated as the stoichiometric 

equivalent of pyraflufen-ethyl. Livestock: the sum of the parent pyraflufen-ethyl and its acid metabolites: E-1and E-9, 2-

chloro-5-(4-chloro-5-difluoromethoxy-1H-pyrazol-3-yl)-4-fluorophenoxyacetic acid, both calculated as the 

stoichiometric equivalent of pyraflufen-ethyl.

US Canada Mexico1 Codex

[40 CFR §180.585(a)] None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Almond, hulls 0.02

Cattle, fat 0.03

Cattle, meat 0.03

Cattle, meat byproducts 0.03

Corn, field, forage 0.01

Corn, field, grain 0.01

Corn, field, stover 0.01

Cotton, gin byproducts 1.5

Cotton, undelinted seed 0.04

Fruit, pome, group 11-10 0.01

Fruit, stone, group 12 0.01

Goat, fat 0.03

Goat, meat 0.03

Goat, meat byproducts 0.03

Grape 0.01

Grass, forage, group 17 1.0

Grass, hay, group 17 1.4

Horse, fat 0.03

Horse, meat 0.03

Horse, meat byproducts 0.03

Milk 0.03

Nut, tree, group 14 0.01

Olive 0.01

Peanut 0.01

Peanut, hay 0.07

Pistachios 0.01

Pomegranate 0.01

Potato 0.02

Sheep, fat 0.03

Sheep, meat 0.03

Sheep, meat byproducts 0.03

Soybean, forage 0.05

Soybean, hay 0.10

Soybean, seed 0.01

Wheat, forage 0.02

Wheat, grain 0.01

Wheat, hay 0.01

Wheat, straw 0.01

Completed: M. Negussie; 01/28/14

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
Page 18 of 25

Attachment 3

Toxicity Endpoint and Point of Departure Selections

Table 3.1. Summary of Toxicological Doses and Endpoints for Pyraflufen-ethyl for Use in Dietary 

and Non-Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

None

An endpoint attributable to a single dose 

was not identified for pyraflufen-ethyl from 

the available data.

Chronic 

Dietary (All 

Populations)

NOAEL = 

20 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Chronic RfD = 

0.20

mg/kg/day

cPAD = 0.2 

mg/kg/day

Mouse Carcinogenicity Study 

LOAEL = 98 mg/kg/day based on liver 

toxicity

Incidental 

Oral ShortTerm (1-30 

days)

NOAEL = 

20 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF = 

1x

Residential LOC 

for MOE = 100

Developmental Toxicity-Rabbit

Maternal LOAEL = 60 mg/kg/day based on 

decreased food consumption and fecal 

output, GI lesions, and premature deaths

Dermal 

Short- (1-30 

days), 

Intermediate 

(1-6 months), 

and Long-

(>6 months) 

Term

None 28-Day Dermal Toxicity – Rats

No dermal or systemic toxicity was seen at 

the Limit Dose (1000 mg/kg/day)

Inhalation 

Short- (1-30 

days) and 

Intermediateand LongTerm (1-6 

months)

NOAEL = 

20 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

Developmental Toxicity-Rabbit

Maternal LOAEL = 60 mg/kg/day based on 

decreased food consumption and fecal 

output, GI lesions, and premature deaths

Cancer (oral, 

dermal, 

inhalation)

Classification: “Likely to be Carcinogenic to Humans” by the oral route.

Q1* = 3.32 x 10-2(mg/kg/day)-1

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = 

population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable. Dermal absorption for cancer assessment assumed to be 100%.
Page 19 of 25

Table 3.2. Summary of Toxicological Doses and Endpoints for Pyraflufen-ethyl for Use in 

Occupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Dermal 

Short- (1-30 

days), 

Intermediate 

(1-6 months), 

and Long-

(>6 months) 

Term

None 28-Day Dermal Toxicity – Rats

No dermal or systemic toxicity was seen at 

the Limit Dose (1000 mg/kg/day)

Inhalation 

Short- (1-30 

days) and 

Intermediateand LongTerm (1-6 

months)

NOAEL = 

20 

mg/kg/day

UFA = 10x

UFH = 10x

FQPA SF= 1x

Residential LOC 

for MOE = 100

Developmental Toxicity-Rabbit

Maternal LOAEL = 60 mg/kg/day based on 

decreased food consumption and fecal 

output, GI lesions, and premature deaths

Cancer (oral, 

dermal, 

inhalation)

Classification: “Likely to be Carcinogenic to Humans” by the oral route.

Q1* = 3.32 x 10-2(mg/kg/day)-1

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of 

concern. N/A = not applicable. Dermal absorption for cancer assessment assumed to be 100%.
Page 20 of 25

Attachment 4

Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses of pyraflufen-ethyl are in Table 4.1. Use of the new guideline 

numbers does not imply that the new (1998) guideline protocols were used.

Table 4.1. Toxicology Data Requirements for Pyraflufen-ethyl.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Acute Eye Irritation .......................................................

870.2500 Acute Dermal Irritation .................................................

870.2600 Skin Sensitization ..........................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 90-Day Oral Toxicity in Rodents ..................................

870.3150 90-Day Oral Toxicity in Nonrodents.............................

870.3200 21/28-Day Dermal Toxicity...........................................

870.3250 90-Day Dermal Toxicity................................................

870.3465 90-Day Inhalation Toxicity ...........................................

yes

yes

yes

no

yes

yes

yes

yes

--

waived4

870.3700a Prenatal Developmental Toxicity (rodent).....................

870.3700b Prenatal Developmental Toxicity (nonrodent)...............

870.3800 Reproduction and Fertility Effects.................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse)................................................

870.4300 Combined Chronic Toxicity/Carcinogenicity................

yes

no

yes

yes

no

yes1

yes2

yes1

yes

yes

870.5100 Mutagenicity—Bacterial Reverse Mutation Test ..........

870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test ..

870.5375 Mutagenicity—Structural Chromosomal Aberrations..

870.5395 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6200a Acute Neurotoxicity Screening Battery (rat) .................

870.6200b 90-Day Neurotoxicity Screening Battery (rat)...............

870.6300 Developmental Neurotoxicity........................................

yes

yes

no

yes

yes

--

870.7485 Metabolism and Pharmacokinetics................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

no3

yes

yes

--

yes

1 The chronic (rodent) and carcinogencity (rat) data requirements are satisfied by the Combined Chronic Toxicity / 

Carcinogenicity study (870.4300).

2

 A chronic study in the dog is available, although it is no longer required.

3 A dermal penetration study is not required because a) a dermal endpoint was not identified (no effects in the 21-day dermal 

study up to the Limit Dose) and b) there were no effects of concern observed in studies such as the developmental and 

reproduction oral studies that reveal adverse effects (such as effects on the offspring) that the 21-day dermal study is not 

designed to detect or measure.

4 The requirement for a subchronic inhalation toxicity study has been waived (TXR#00564072)
Page 21 of 25

Table 4.2. Acute Toxicity of Pyraflufen-ethyl.

Guideline

No.

Study Type MRID # Results Toxicity Category

870.1100 Acute Oral 45327615 LD50 > 5000 mg/kg IV

870.1200 Acute Dermal 45327613 LD50 > 2000 mg/kg III

870.1300 Acute Inhalation 45282821 LC50 > 5.03 mg/L IV

870.2400 Primary Eye Irritation 45327614 moderate irritation III

870.2500 Primary Skin Irritation 45282823 no irritation IV

870.2600 Dermal Sensitization 45282824 non-sensitizing N/A

Table 4.3. Non-acute Toxicity Profile for Pyraflufen-Ethyl.

Guideline Number 

and Study Type

MRID (Year)

Dose Levels Results

870.3100

13-Week 

Oral Feeding Rat 

45282903 (1994)

0, 200, 1000, 5000, 15000 ppm 

M;0, 17.8, 85.6,456, 1489 mg/kg/day 

F: 0, 19.4, 95.4, 499, 1503 mg/kg/day 

Acceptable/guideline

NOAEL = 456-499 mg/kg/day.

LOAEL = 1489-1503 mg/kg/day) based on clinical signs, death, effects on 

erythrocytes, changes in clinical chemicals for liver function and 

splenomegaly

870.3150

13-Week 

Oral Capsule Dog 

45282905 (1996)

0, 40, 200 or 1000 mg/kg/day

Acceptable/guideline

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

870.3200

28-Day Dermal Rat

45283001 (2000)

0, 100, 300 or 1000 mg/kg/day

Acceptable/guideline

NOAEL = 1000 mg/kg/day

LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

870.3700a

Developmental 

Toxicity Rats

45282917 (1995)

0, 100, 300 or 1000 mg/kg/day

Acceptable/guideline

Maternal NOAEL = 1000 mg/kg/day.

Maternal LOAEL > 1000 mg/kg/day. No effects observed at Limit Dose.

Developmental NOAEL = 1000 mg/kg/day.

Developmental LOAEL > 1000 mg/kg/day. No effects observed at Limit 

Dose.

870.3700b

Developmental 

Toxicity Rabbit

45282918 (1996)

0, 20, 60 or 150 mg/kg/day

Acceptable/guideline

Maternal NOAEL = 20 mg/kg/day. 

Maternal LOAEL= 60 mg/kg/day based on reduced food intake and 

fecal output, lesions in the gastrointestinal tract, and premature 

deaths.

Developmental NOAEL = 60 mg/kg/day.

Developmental LOAEL = 150 mg/kg/day based on increased incidence of 

abortion.
Page 22 of 25

Table 4.3. Non-acute Toxicity Profile for Pyraflufen-Ethyl.

Guideline Number 

and Study Type

MRID (Year)

Dose Levels Results

870.3800

2-Generation 

Reproduction Rat 

45282922 (1996)

0, 100, 1000 or 10, 000 ppm 

0, 6.84, 70.8 and 721 mg/kg/day (F0[M]); 

0, 7.78, 80.1 and 813 mg/kg/day (F0[F]); 

0, 8.10, 82.3 and 844 mg/kg/day (F1[M]); 

0, 9.06, 91.2 and 901 mg/kg/day (F1[F])

Acceptable/guideline

Parental NOAEL = 70.8-82.3 mg/kg/day [M]; 80.1-91.2 [F].

Parental LOAEL = 721-844 and 813-901 mg/kg/day based on decreased 

body wt and body wt gains of F0 and F1(M) and F1(F), gross and 

microscopic liver lesions of (M) and (F)-both generations.

Reproductive NOAEL = 721-844 and 813-901 mg/kg/day.

Reproductive LOAEL not determined. No effects observed.

Offspring NOAEL = 70.8-82.3 mg/kg/day [M]; 80.1-91.2 [F].

Offspring LOAEL = 721-844 and 813-901 mg/kg/day based on decreased 

body weight and body weight gains of the F1 and F2 pups.

870.4300

2-yr Chronic/ 

Carcino-genicity 

Rat

45282911 (1996)

0, 80, 400, 2000 or 10,000 ppm 

0, 3.4, 17.2, 86.7 and 468.1 mg/kg/day 

(M)

0, 4.4, 21.8, 11.5 and 578.5 mg/kg/day 

(F)

Acceptable/guideline

NOAEL = 86.7 mg/kg/day (M); 111.5 mg/kg/day (F).

LOAEL = 468.1 mg/kg/day(M); 578.5 mg/kg/day (F) based on decreased 

body weight and body weight gain in males and microcytic anemia, liver 

lesions and kidney toxicity (both sexes); possible increase 

pheochromocytomas in females

870.4200b

78-Week Carcinogenicity Mouse

45282913 (1996)

0, 200, 1000 or 5000 ppm 

0, 20.99, 109.7 and 546.8 mg/kg/day (M)

0, 19.58, 98.3, and 523.7 mg/kg/day (F)

Acceptable/guideline

NOAEL = 20.99 mg/kg/day (M); 19.58 mg/kg/day (F).

LOAEL = 109.7 mg/kg/day (M); 98.3 mg/kg/day (F) based on liver 

toxicity, hepatocellular tumors at 5,000 ppm; possibly hemangioma/ 

hemangioasarcomas.

870.4100b

52-Week Oral 

Feeding Dogs

45282906 (1996)

0, 40, 200 or 1000 mg/kg/day

Acceptable/guideline

NOAEL = 1000 mg/kg/day. 

LOAEL > 1000 mg/kg/day; no effects observed.

870.5100

Bacterial Reverse 

Gene Mutation 

Assay

45282924 (1994), 

0, 156.3, 312.5, 625, 1250, 2500, 5000 

μg/plate in the presence and absence of 

mammalian metabolic activation (S9-

mix) in two independent assays.

Acceptable/guideline

There was no evidence of induced mutant colonies over background.

870.5300

In Vitro

Mammalian Cell 

Gene Mutation 

Assay (mouse 

lymphoma)

45327623 (1994)

0, 10, 20, 30, 40 or 50 μg/mL for 4 hours 

in the absence of mammalian metabolic 

activation (S9-mix). 

0, 150, 200, 250, 300 or 350 μg/mL for 4 

hours with S9-mix. Two independent 

assays were conducted.

Acceptable/guideline

There was no evidence of induced mutant colonies over background up to 

cytotoxic concentrations (50 μg/ml -S9; 350 μg/ml +S9).
Page 23 of 25

Table 4.3. Non-acute Toxicity Profile for Pyraflufen-Ethyl.

Guideline Number 

and Study Type

MRID (Year)

Dose Levels Results

870.5300

In Vitro

Mammalian Cell 

Gene Mutation 

Assay (mouse 

lymphoma)

45282928 (1984),

Assay 1

0, 10, 20, 40, 60 or 80 μg/mL for 4 hours 

in the absence of mammalian metabolic 

activation (S9-mix).

0, 20, 40, 80, 120 or 160 μg/mL for 4 

hours with S9-mix. 

Assay 2

0, 20, 40, 60, 80 or 100 μg/mL without 

S9-mix

0, 40, 80, 120, 160 or 200 μg/mL with 

S9-mix 

Acceptable/guideline

There was no increase in the number of mutant colonies over background 

in the absence of S9-mix but a non-reproducible dose-related increase in 

the number of mutant colonies was seen in the presence of S9-mix.

870.5375

In Vitro

Mammalian 

Chromosome 

Aberration

45282927 (1994)

0, 650, 1300 or 2600 μg/mL for 19 or 43 

hours without metabolic activation (S9-

mix) or for three hours with S9-mix. 

A second assay was conducted at the 

same three concentrations but using a 19 

hour sampling time only.

Acceptable/guideline

There was no evidence of chromosomal aberration induction over 

background.

870.5500

Bacterial DNA 

Damage and Repair

45282929 (1994)

0, 343.75, 687.5, 1375, 2750 or 5500 

μg/disk in the presence and absence of 

metabolic activation (S9-mix). 

Acceptable/guideline

There was no evidence of greater growth inhibition or cell killing in repairdefective strains compared to repair competent strains up to the limit of 

test material solubility.

870.5550

in vivo/in vitro

unscheduled DNA 

Synthesis (UDS) 

45282930 (1998)

600 and 2000 mg/kg 

Acceptable/guideline

The mean net nuclear grain count was below zero for both doses at both 

treatment times indicating no induction of UDS as tested in this study.

870.5395

Mouse 

Micronucleus 

Assay

45282931(1994)

a single dose at 0, 1250, 2500 or 5000 

mg/kg with sacrifice at 24 hours; 

a single dose of 5000 mg/kg with 

sacrifice at 48 and 72 hours; 

two doses of 2500 or 5000 mg/kg 

separated by 24 hours with sacrifice 24 

hours after the second dose

Acceptable/guideline

There was no statistically significant increase in the frequency of 

micronucleated polychromatic erythrocytes in bone marrow after any dose 

or treatment time.

870.6300a

Acute 

Neurotoxicity Rat

48802401 (2012)

0, 125, 500 or 2000, mg/kg

Acceptable/guideline

NOAEL = 500 mg/kg

LOAEL = 2000 mg/kg based on transiently decreased body weight gain in 

females (↓26%, ns). No neurotoxicity was observed.
Page 24 of 25

Table 4.3. Non-acute Toxicity Profile for Pyraflufen-Ethyl.

Guideline Number 

and Study Type

MRID (Year)

Dose Levels Results

870.6300b

Subchronic

Neurotoxicity Rat

48802402 (2012)

0, 1000, 2800, 8000 ppm

(M) 0, 61, 174, 502 mg/kg/day

(F) 0, 80, 222, 625 mg/kg/day

Acceptable/guideline

NOAEL = 61 mg/kg/day (M), 222 mg/kg/day (F)

LOAEL = 174 mg/kg/day (M), 625 mg/kg/day (F) based on transient 

decrease in body weight gain and changes in hematology parameters. No 

neurotoxicity was observed.

870.7485

Metabolism and 

Pharmaco-kinetics 

Rat

45282932, 45282933, 45282934, 

45282935 (1996)

5.0, 500 mg/kg single oral dose

5 mg/kg/day 14-day repeated oral dose

Acceptable/guideline 

ET-751(pyraflufen-ethyl) was readily absorbed and excreted within 96 

hours following a single or repeated oral dose of 5 mg/kg (plasma t1/2 of 3-

3.5 hrs). However, at a dose of 500 mg/kg, absorption was saturated as 

indicated by Cmax values which did not reflect the 100-fold dose 

differential (2.7-2.8 μg eq/g for the low-dose group and 100-107 μg eqhr/g for the high-dose group). Following single or multiple oral low doses 

(5 mg/kg) of ET-751, urinary excretion accounted for 27-33% of the 

administered radioactivity suggesting that a multiple exposure regimen did 

not affect the absorption/excretion processes. Urinary excretion was 

reduced to only 5-7% following a single 500 mg/kg dose. Excretion via 

the feces accounted for the remainder of the administered radioactivity in 

all treatment groups. Analysis of biliary excretion following a single 5 

mg/kg dose showed that 36% of the administered dose appeared in the 

bile. Based upon the excretion data, total bioavailability of a low dose was 

approximately 56%. Biliary excretion data were not available for a highdose group which prevented a definitive assessment of bioavailability. 

Excretory patterns did not exhibit gender-related variability. However, 

plasma and blood clearance was more rapid in females than in males as 

shown by plasma/blood radioactivity time-course and the greater AUC 

values for males (32.3 vs 18.4 μg eq-hr/g for the low-dose group and 2738 

vs 1401 μg eq-hr/g for the high-dose group). Radioactivity concentrations 

indicated tissue concentrations at or near detection limits (generally <0.01 

μg eq/g and never exceeding 0.02 μg eq/g) at 96 hrs postdose for any 

tissues. Therefore, neither ET-751 nor its metabolites appear to undergo 

significant sequestration. Tissue burden data following compound 

administration did not suggest a specific target beyond those tissues, 

namely liver and kidney, which are associated with absorption and 

elimination of orally administered xenobiotics.

Both urinary and fecal metabolites were quantified by HPLC and most 

were identified using HPLC and TLC in conjunction with known 

standards. The metabolites identified (primarily hydrolysis and subsequent 

demethylation products) were consistent with Phase I processes. The 

major metabolic pathway appears to be a sequential hydrolysis and 

demethylation of the parent compound to metabolites E-1 and E-9 both of 

which are quantitatively prominent components detected in the urine and 

feces from all treatment groups. Extraction efficiencies appeared to be 

excellent and most components in all of the matrices examined (urine, 

feces, plasma, and bile) were adequately quantified and characterized. The 

available data, based upon studies using both the pyrazole-5 and the 

uniformly labeled phenyl ring, affirmed the metabolism pathway proposed 

by the investigators.
Page 25 of 25

Table 4.3. Non-acute Toxicity Profile for Pyraflufen-Ethyl.

Guideline Number 

and Study Type

MRID (Year)

Dose Levels Results

870.7800

Immunotoxicity 

Rat

48577901 (2011)

0, 750, 3000 or 12,000 ppm 

0, 59.4, 236.2, 946.2 mg/kg/day (M)

0, 67.1, 277.5, 1114.0 mg/kg /day (F)

Acceptable/guideline

Systemic Toxicity 

NOAEL= 236.2 mg/kg/day (M); 1114.0 mg/kg /day (F)

LOAEL = 946.2 mg/kg/day (M) based on decreases in body weight, body 

weight gain, food consumption and feed efficiency; not established in (F).

Immunotoxicity 

NOAEL= 236.2 mg/kg/day (M); 1114.0 mg/kg /day) (F)

LOAEL = 946.2 mg/kg/day (M) based on decreases of anti-SRBC AFC 

response; not established in (F).